EP1115687B1 - 5,6-dihydronaphthalenyl derivatives having retinoid-like activity - Google Patents
5,6-dihydronaphthalenyl derivatives having retinoid-like activity Download PDFInfo
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- EP1115687B1 EP1115687B1 EP99948322A EP99948322A EP1115687B1 EP 1115687 B1 EP1115687 B1 EP 1115687B1 EP 99948322 A EP99948322 A EP 99948322A EP 99948322 A EP99948322 A EP 99948322A EP 1115687 B1 EP1115687 B1 EP 1115687B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
Definitions
- the present invention provides a series of 5,6-dihydronaphthalenyl derivatives which exhibits unexpectedly good therapeutic indexes in the treatment of skin disorders such as, but not limited to, acne and damage from age or irradiation and chronic skin inflammatory diseases such as psoriasis and atopic dermatitis.
- skin disorders such as, but not limited to, acne and damage from age or irradiation and chronic skin inflammatory diseases such as psoriasis and atopic dermatitis.
- the compounds are also useful as antitumor agents for the treatment of, but not limited to, breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, blood and lymphatic system cancers.
- compositions having a retinoid-like compound are useful for treating and/or preventing skin-related diseases such as, but not limited to acne, actinic keratosis, psoriasis, eczema and atopic dermatitis. It is also known that they are useful to reverse or treat the effects of age and photo damage to the skin and to prevent and/or treat cancerous or precancerous conditions.
- retinoids One of the most significant drawbacks associated with the use of retinoids, especially in the topical treatment of dermatological diseases, is local irritation. Retinoids or compounds having retinoid-like activity that combine good topical efficacy and cutaneous tolerability are not very common. Recently, the new drug adapalene (“Differin", CIRD Galderma) was reported to offer these favorable characteristics and it has been launched in several countries as a water-based gel formulation.
- U.S. Pat. No. 5,648,514 describes a series of substituted (5,6)-dihydronaphthalene derivatives having retinoid-like biological activity of the formula wherein R 1 is hydrogen or alkyl of 1 to 10 carbons; R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0-3; o is an integer having the value 0-3; Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups; A is (CH 2 ) n where n is 0-5, lower
- That disclosure is specifically limited to the ethynyl linker.
- the two compounds disclosed in the present invention have the ethenyl linker.
- the substituent in position 8 (R 22 ) is defined as being, among others, an alkenyl group of 2 to 10 carbons and having 1 to 3 double bonds or an alkynyl group having 2 to 10 carbons and 1 to 3 triple bonds. This general definition does not specify the direct attachment to the dihydronaphthalene nucleus at position 8.
- X 1 is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
- R 2 is hydrogen, lower alkyl of 1 to
- R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
- R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
- R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
- R 11 is lower alkyl, phenyl or lower alkylphenyl
- R 12 is lower alkyl
- R 13 is divalent alkyl radical of 2-5 carbons
- R 14 is (R 15 ) r - substituted alkyl of 1-6 carbons, (R 15 ) r - substituted alkenyl of 1-6 carbons and 1 or 2 double bonds
- WO 97/48672 generally discloses these compounds having retinoid-like activity and as agents for preventing or treating cancerous and precancerous conditions.
- the assay supporting this statement is a measure of the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA) induction of ornithine decarboxylase (ODC) in mouse epidermis by certain compounds disclosed in application. TPA-induced ODC activity is known to occur at pre-malignant stages.
- the present invention provides (5,6)-dihydronaphthalenyl compounds having retinoid-like activity and the structural formula or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof. They have unexpectedly low-irritancy profiles and are useful in the treatment of skin disorders such as, but not limited to, acne and damage from age or irradiation and chronic skin inflammatory diseases such as psoriasis and atopic dermatitis or as antitumor agents for the treatment of breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, blood and lymphatic system cancers.
- skin disorders such as, but not limited to, acne and damage from age or irradiation and chronic skin inflammatory diseases such as psoriasis and atopic dermatitis or as antitumor agents for the treatment of breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung
- the present invention relates to the compounds of formula or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof.
- Compounds of formula I and II may form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the compound. These salts are part of the present invention.
- Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred.
- Amines which are capable of forming stable salts include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N.N'-dibenzytethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine or dicyclohexylamine.
- the compounds of formula I and II can also form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I or II compounds per se . They are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood.
- physiologically hydrolyzable esters of compounds of formula I include C 1-6 alkyl benzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C 1-6 alkanoyloxy-C 1-6 alkyl, e.g.
- esters used, for example, in the penicillin and cephalosporin arts. Such esters are prepared by conventional techniques known in the art.
- the compounds of formula I and II above may be used topically or systemically, as anticancer agents and in the treatment, amelioration or prevention of skin disorders.
- they may be used for therapy in mammals, including humans, of premalignant epithelial cell lesions, as a prophylaxis against tumor promotion in epithelial cells and treatment for dermatoses such as ichthyoses, follicular disorders, benign epithelial disorders and other proliferative skin diseases such as psoriasis, eczema, atopic dermatitis or non-specific dermatosis. They may also be used in reversing and preventing the effects of irradiation damage to skin.
- a pharmaceutical acceptable carrier is a material that is nontoxic and generally inert and does not adversely affect the functionality of the active ingredients. Such materials are well known and include those materials sometimes referred to as diluents or vehicles (excipients) in the pharmaceutical formulation art.
- the carrier may be organic or inorganic in nature.
- Examples of pharmaceutically acceptable carriers that may be used to formulate a compound of formula I or II are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, orbital, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers.
- the formulation may contain minor amounts of additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
- the dosages and dosage regimen in which the compounds of formula I and II are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation.
- the drug In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases oral administration may also be used. If the compounds according to the invention are used topically, it will be found that they exhibit a good activity over a very broad range of dilution; in particular, concentrations of the active compound or compounds ranging from 0.0005% to 2% by weight can generally be used. It is of course possible to use higher concentrations if this should become necessary for a particular application; however, the preferred concentration of active principle are from 0.002% to 1% by weight.
- the compounds of formula I and II are conveniently provided in the form of unguents, gels, creams, ointments, powders, dyeing compositions, solutions, suspension, emulsions, lotions, sprays, adhesive plasters and impregnated pads.
- the compounds according to the invention can be mixed with inert nontoxic, generally liquid or pasty, bases suitable for topical treatment. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. Other medicaments can be added to such formulation for such secondary purposes as treating skin dryness, providing protection against light; other medications for treating dermatoses, preventing infection, reducing irritation or inflammation.
- the compounds according to the invention can also be used enterally.
- the compounds according to the invention are suitable administered at the rate of 100 mg to 100 mg per day per kg of body weight.
- the required dose can be administered in one or more portions.
- suitable forms are, for example, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using pills containing from 1 mg to about 1000 mg of active substance.
- U.S. Patent No. 4,876,381 issued on October 24, 1989 to Lang et al. provides examples of formulations constituting gel, unguent, powder, cream, etc.
- the aforesaid U.S. patent can be used as a guide to formulate a compound of formula I and II.
- Isotretinoin (Accutane) and etretinate (Tegison”) are used clinically to treat severe recalcitrant cystic acne and severe recalcitrant psoriasis, including the erythrodermica and generalized pustular types, respectively. Their mode of use is amply illustrated in the Physician's Desk Reference, 47th Edition (1993), published by Medical Economics Data. The compounds of formula I and II may also be used to treat severe recalcitrant psoriasis.
- the compounds of the present invention may be used in a similar fashion to isotretinoin and etretinate; thus, the relevant sections on isotretinoin and etretinate in the Phvsician's Desk Reference will serve as a convenient guide which will obviate the need for any undue experimentation.
- the compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections.
- the compounds according to the invention are generally administered at the rate of about 10 mg to 10 mg per day per kg of body weight; a preferred method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml.
- retinoids have been found to possess anti-tumor properties. Roberts, A.B. and Sporn, M.B. in The Retinoids, Sporn, M.B., Roberts, A.B., and Goodman, D.S., eds., 2, p. 209-286 (1984), Academic Press, New York; Lippman, S.M., Kessler, J.F., and Meyskens, F.L., Cancer Treat. Rep., 71, p. 391 (1987); ibid., p. 493.
- anti-tumor includes both chemopreventive (prophylactic or tumor promotion inhibiting) and therapeutic (curative) use.
- all-trans retinoic acid can be used to treat acute promyelocytic leukemia.
- Isotretinoin has been shown to be useful in prevention of second primary tumors in squamous-cell carcinoma of the head and neck.
- the compounds of formula I and II can be used in a substantially similar manner to retinoids for treating (both chemopreventively and therapeutically) various tumors.
- the anti-tumor dose to be administered whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient, the type of tumor, and the nature of the patient's condition.
- the dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
- an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention, such as by referring to the earlier published studies on retinoids found to have anti-tumor properties.
- an oncologist may refer to the study by Hong, W.K. et al. in N. Engl. J. Med., 323, p. 795 (1990).
- the oncologist may refer to the study by Huang, M. et al. in Blood, 72, p. 567 (1988).
- retinoid-like activity and efficacy of these compounds has been confirmed by a retinoid transactivation assay described in Skin Pharmacology. 8, p. 292-299 (1995).
- HeLa cells are co-transfected with DNA encoding RAR ⁇ , ⁇ or ⁇ , and an RAR-responsive CAT reporter gene.
- Retinoid efficacy is measured by the concentration of induced CAT gene product as determined by ELISA assay.
- the compounds of the present invention have shown activity as agonist or partial agonist in at least one of the three receptor subtypes ( ⁇ , ⁇ , ⁇ ).
- the apparent Kds for binding of these compounds to the three RAR receptors have been also evaluated by an assay described in Skin Pharmacology, 8, p.
- the comedolytic activity of the compounds of the instant application has been evaluated by the rhino mouse assay model.
- the compounds were administered daily to rhino mice topically in ethanol at various concentrations for 5 days. Signs of skin irritation are evaluated at day 5 by visual inspection of the mouse skin and graded for edema, erythema (redness) and scaling (flakiness) with scales of 1-5 and 1-4, respectively. Skin samples were taken at day 7 and processed for image analysis to measure the size of utriculi.
- Table 2 provides the percent of inhibition at two different concentrations of the compounds I and II of the present invention as well as some other compounds generically disclosed by the patent application WO 97/48672.
- the irritation study of the retinoid compounds of this invention was also performed with a more sensitive animal model, i.e., the rabbit skin irritation model.
- the compounds were applied topically daily to rabbit skin for 14 days in ethanol vehicle.
- the animals were graded daily for signs of irritation, i.e., edema, erythema and scaling, which are typical of retinoid effects on the skin.
- the total irritation score over the 14 day period was used to obtain the area under the curve (AUC).
- Table 3 shows the erythema score of the compounds I and II of the present invention, as well as the erythema score of some other compounds generically disclosed in the patent application WO 97/48672. It can be noticed that for compounds I and II, the irritation and inflammation usually seen with retinoids administered topically, was not observed. It is worthy of note that many other compounds of the patent application WO 97/48672 were found to be irritating. This demonstrates that the compounds of the present invention are unexpectedly devoid of skin irritation which is not a common characteristic of compounds having retinoid-like activity and could not be predicted for such compounds.
- the compounds of the present invention have been also tested as inhibitors of cell proliferation ( 3 H-thymidine uptake).
- Cells were plated on 96-well plates at a pre-determined density so that 80% cellular confluency is reached by day 7. 24 hr after plating, culture media was changed and cells were treated with the appropriate drug or vehicle (day 0). Culture media was changed on days 3 and 6. Cellular proliferation was measured on Day 7 by quantitating the amount of tritiated thymidine ([3H]-TdR) incorporated into the celular DNA (Odham, K.G. (1977) in: Radiotracer Techniques and Applications, edited by E.A. Evans and M. Murawatsu; M. Dekker Inc. New York; 2, 823).
- Table 4 shows the ED30 values of topical activity as well as a measure of the concentration necessary to achieve an irritation score of 3 (IS3) for the compounds I and II of the present invention and the compounds generically disclosed in the patent application WO 97/48672.
- Compound I which did not show any signs of irritation at 5 mM has a therapeutic index highly superior to TRA and to most of the closely related analogs disclosed in WO 97/48672.
- Compound I of the present invention unlike its closely related analogs is unexpectedly unique in that aspect.
- Table 5 provides the IC 50 values of some representative compounds in various carcinoma cell lines.
- the compounds of the present invention showed potent anti-proliferative activity.
- V volume (mm3)
- l measurement of longest axis (mm)
- w measurement of axis perpendicular to I.
- Compound I when administered intraperitoneally every two days for 10 days, is as potent as doxorubicin in that model in inhibiting tumor growth as shown in Fig 3 and Table 5.
- the tumor growth delay was equivalent to 1.2 log cell kill at 30 mg/kg.
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Abstract
Description
R1 is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus;
m is an integer having the value of 0-3;
o is an integer having the value 0-3;
Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups;
A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, COR7, CR7(OR12)2, CR7OR13O, or trilower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and
R22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl, C1-C10 alkyl, naphthyl-C1-C10alkyl, C1-C10-alkenylphenyl having 1 to 3 double bonds, C1-C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1-C10alkenyl having 1 to 3 double bonds, phenyl-C1-C10alkynyl having 1 to 3 triple bonds, hydroxyalkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where the acyl group is represented by COR14, CN, CON(R1)2, (CH2)pCO2R8 where p is an integer between 0 to 10, or R22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C1 to C10 alkyl group and having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R22 is represented by (CH2)pXR1 or by (CH2)pNR1R2; where X is O or S, the R14 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, or naphthyl-C1-C10alkyl.
Z is
-N=N-,
-N(O)=N-,
-N=N(O)-,
-N=CR1-,
-CR1=N,
-(CR1=CR1)n'- where n' is an integer having the value 0 to 5,
-CO-NR1-,
-CS-NR1-,
-NR1-CO-,
-NR1-CS-,
-COO-,
-OCO-,
-CSO-,
-OCS-,
-CO-CR1=CR1-;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0 to 3;
o is an integer having the value of 0 to 3;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is -(CR1=CR1)n,- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR2=CR2)n' group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or Si(C1. 6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and
R14 is (R15)r- substituted alkyl of 1-6 carbons, (R15)r- substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R15)r-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, COOH, COOR8 and alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons.
Compound | Kd (α) nM | Kd (β) nM | Kd (γ) nM |
I | 2.23 | 1.26 | 25 |
II | 1.60 | 2.19 | 1.57 |
TRA | 0.6 | 0.6 | 0.28 |
1H NMR 400 MHz (CDCl3) δ (ppm): 1.34 (6H, S, 2 x -CH3), 2.45 (2H, d, J=4.8 Hz, H-6'), 3.94 (3H, s, -OCH3), 6.02 (1H, t, J=4.8 Hz, H-7'), 7.13 (1H, d, J=16.3 Hz, vinyl H), 7.22 (1H, d, J=16.3 Hz, vinyl H), 7.34 (1H, d, J=8.0 Hz, H-4'), 7.51 (1H, dd, J=8.0 and 1.6 Hz, H-3'), 7.54 (1H, br s, H-1'), 7.59 (2H, d, J=8.3 Hz, H-3 and H-5), 8.05 (2H, d, J=8.4 Hz, H-2 and H-6).
IR (KBr) υmax (cm-1): 2985, 1715 (C=O), 1605.
1H NMR 400 MHz (CDCL3) δ (ppm): 1.30 (6H, s, 2 x -CH3), 1.42 (9H, S, -tBu), 2.32 (2H, d, J=4.8 Hz, H-6'), 3.94 (3H, s, -OCH3), 6.33 (1H, t, J=4.8 Hz, H-7'), 7.13 (1H, d, J=16.3 Hz, vinyl H), 7.23 (1H, d, J=16.3 Hz, vinyl H), 7.30 (1H, d, J=7.9 Hz, H-4'), 7.39 (1H, dd, J=7.9 and 1.7 Hz, H-3'), 7.56 (2H, d, H-3 and H-5), 7.85 (1H, d, J=1.6 Hz, H-1'), 8.04 (2H, d, J=8.3 Hz, H-2 and H-6).
Anal. Calcd, for C28H30O2 | C 84.38; | H 7.59. |
Found | C 83.95; | H 7.69. |
IR (KBr) υmax (cm-1): 3650-2000 (br), 2825,1670 (C=O), 1600.
1H NMR 400 MHz (DMSO-d6) δ (ppm): 1.22 (6H, s, 2 x -CH3), 1.37 (9H, s, -tBu), 2.28 (2H, d, J=4.8 Hz, H-6'), 6.31 (1H, t, J=4.8 Hz, H-7'), 7.20 (1H, d, J=16.4 Hz, vinyl H), 7.36 (1H, d, J=8.0 Hz, H-4'), 7.41 (1H, d, J=16.4 Hz, vinyl H), 7.55 (1H, dd, J=8.0 and 1.7 Hz, H-3'), 7.71 (2H, d, J=8.3 Hz, H-3 and H-5), 7.72 (1H, br s, H-1'), 7.94 (2H, d, J=8.3 Hz, H-2 and H-6).
Anal. Calcd. for C27H28O2 | C 84.34; | H 7.34. |
Found | C 84.22; | H 7.23. |
IR (CH2Cl2) υmax (cm-1): 1716 (C=O), 1604.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.04 (2H, d, J=8.3 Hz, H-2 and H-6), 7.76 (1H, br s, H-1'), 7.57 (2H, d, J=8.3 Hz, H-3 and H-5), 7.43 (1H, br d, J=8.0 Hz, H-3'), 7.32 (1H, d, J=8.0 Hz, H-4'), 7.23 and 7.12 (2 x 1H, 2 d, J=16.3 Hz, vinyl H), 6.42 (1H, t, J=4.8 Hz, H-7'), 3.94 (3H, s, -OCH3), 2.34 (2H, d, J=4.8 Hz, H-6'), 2.05 (1H, br s, -OH), 1.71 (6H, s, 2 x -CH3), 1.30 (6H, s, 2 x -CH3).
1H NMR 400 MHz (CDCl3) δ (ppm): 8.03 (2H, d, J=8.3 Hz, H-2 and H-6), 7.58 (2H, d, J=8.3 Hz, H-3 and H-5), 7.43 (1H, dd, J=8.0 and 1.8 Hz, H-3'), 7.39 (1H, d, J=1.6 Hz, H-1'), 7.35 (1H, d, J=7.9 Hz, H-4'), 7.21 and 7.08 (2 x 1H, 2 d, J=16.3 Hz, vinyl H), 6.15 (1H, dq, J=12.4 and 2.1 Hz, -CH=CH(CH3)2OH), 5.98 (1H, m, H-7'), 5.91 (1H, d, J=12.4 Hz,-CH=CH(CH3)2OH), 3.94 (3H, s, -OCH3), 2.33 (2H, dd, J=4.4 and 2.6 Hz, H-6'), 1.41 and 1.31 (2 x 6H, 2 S, 4 x -CH3).
IR (nujol) υmax (cm-1): 2924, 2855, 1681 (C=O), 1604.
1H NMR 400 MHz (DMSO-d6) δ (ppm): 7.92 (2H, d, J=8.1 Hz, H-2 and H-6), 7.72 (2H, d, J=8.2 Hz, H-3 and H-5), 7.52 (1H, br d, J=8.0 Hz, H-3'), 7.40-7.36 (3H, m, vinyl H, H-1' and H-4'), 7.21 (1H, d, J=16.4 Hz, vinyl H), 6.03 (1H, br d, J=12.5 Hz, -CH=CH(CH3)2OH), 5.89 (1H, br s, H-7'), 5.87 (1H, d, J=12.5 Hz, -CH=CH(CH3)2OH), 2.25 (2H, br s, H-6'), 1.25 (12H, s, 4 x -CH3).
Anal. Calcd. for C26H28O3 | C 80.38; | H 7.27. |
Found | C 80.47; | H 6.96. |
IR (KBr) υmax (cm-1): 2960, 2915, 2860, 1685 (C=O).
1H NMR 400 MHz (CDCl3) δ (ppm): 8.12 (1H, d, J=2.2 Hz, H-8), 7.62 (1H, dd, J=8.4 and 2.2 Hz, H-6), 7.30 (1H, d, J=8.4 Hz, H-5), 2.87-2.78 (1H, m, H-2), 1.92-1.86 (2H, m, H-3), 1.42 and 1.38 (2 x 3H, 2 s, 4-CH3), 1.26 (3H, d, J=6.6 Hz, 2-CH3).
Anal. Calcd. for C13H15BrO | C 58.44; | H 5.66. |
Found | C 58.59; | H 5.62. |
m.p.: 157°C.
IR (KBr) υmax (cm-1): 2960, 2930, 2865, 1710, 1685 (C=O), 1600.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.17 (1H, d, J=2.0 Hz, H-1'), 8.04 (2H, d, J=8.4 Hz, H-2 and H-6), 7.69 (1H, dd, J=8.2 and 2.0 Hz, H-3'), 7.58 (2H, d, J=8.4 Hz, H-3 and H-5), 7.44 (1H, d, J=8.2 Hz, H-4'), 7.24 (1H, d, JAB=16.4 Hz, vinyl H), 7.20 (1H, d, JAB=16.4 Hz, vinyl H).3.94 (3H, s, -OCH3), 2.91-2.81 (1H, m, H-7'), 1.94 (2H, d, J=9.0 Hz, H-6'), 1.45 and 1.41 (2 x 3H, 2 s, 5'-CH3), 1.29 (3H, d, J=6.6 Hz, 7'-CH3).
Anal. Calcd. for C23H24O3 | C 79.28; | H 6.94. |
Found | C 78.99; | H 6.92. |
IR (KBr) υmax (cm-1): 2980, 2960, 1720, (C=O), 1610.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.04 (2H, d, J=8.3 Hz, H-2 and H-6), 7.58 (2H, d, J=8.3 Hz, H-3 and H-5), 7.52 (1H, br s, H-1'), 7.44 (1H, br d, J=8.0 Hz, H-3'), 7.30 (1H, d, J=8.0 Hz, H-4'), 7.20 (1H, d, J=16.3 Hz, vinyl H), 7.11 (1H, d, J=16.3 Hz, vinyl H), 3.94 (3H, s, -OCH3), 2.35 (2H, s, H-6'), 2.02 (3H, s, -CH3-7'), 1.33 (6H, S, 2 x -CH3-5').
Anal. Calcd. for C24H23F3O5S | C 59.99; | H 4.83. |
Found | C 60.15; | H 4.80. |
IR (KBr) υmax (cm-1): 2980, 2910, 2870,1718, (C=O), 1610.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.03 (2H, d, J=8.4 Hz, H-2 and H-6), 7.84 (1H, d, J=1.7 Hz, H-1'). 7.56 (2H, d, J=8.4 Hz, H-3 and H-5), 7.34 (1H, dd, J=7.8 and 1.7 Hz, H-3'), 7.27 (1H, d, J=7.8 Hz, H-4'), 7.23 (1H, d, J=16.3 Hz, vinyl H), 7.12 (1H, d, J=16.3 Hz, vinyl H), 3.94 (3H, s, -OCH3), 2.25 (2H, s, H-6'), 2.14 (3H, s, -CH3-7'), 1.43 (9H, s, -tBu), 1.26 (6H, s, 2 x -CH3).
Anal. Calcd. for C29H32O2 | C 84.42; | H 7.82. |
Found | C 84.05; | H 7.91. |
IR (KBr) υmax (cm-1): 2975, 2960, 1670 (C=O), 1605.
1H NMR 400 MHz (DMSO-d6) δ (ppm): 12.90 (1H, s, -CO2H), 7.94 (2H, d, J=7.9 Hz, H-2 and H-6), 7.71 (2H, d, J=7.9 Hz, H-3 and H-5), 7.71 (1H, br s, H-1'), 7.49 (1H, d, J=8.0 Hz, H-3'), 7.40 (1H, d, J=16.4 Hz, vinyl H), 7.32 (1H, d, J=8.0 Hz, H-4'), 7.19 (1H, d, J=16.4 Hz, vinyl H), 2.24 (2H, s, H-6'), 2.09 (3H, s, -CH3-7'), 1.39 (9H, s, -tBu), 1.20 (6H, s, 2 x -CH3).
Anal. Calcd. for C28H30O2 . 0.2 H2O | C 83.63; | H 7.62. |
Found | C 83.52; | H 7.50. |
IR (CH2Cl2) υmax (cm-1): 2950, 1705 (C=O), 1595.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.03 (2H, d, J=8.4 Hz, H-2 and H-6), 7.58 (2H, d, J=8.4 Hz, H-3 and H-5), 7.41 (2H, m, H-1' and H-3' or H-4'), 7.34 (1H, m, H-3' or H-4'), 7.22 (1H, d, J=16.3 Hz, vinyl H), 7.08 (1H, d, J=16.3 Hz, vinyl H), 6.00 (1H, dq, J=12.4 and 2.2 Hz, -CH=CH-tBu), 5.84 (1H, td, J=4.4 and 1.8 Hz, H-7'), 5.73 (1H, d, J=12.4 Hz, -CH=CH-tBu), 3.94 (3H, s, -OCH3), 2.30 (2H, dd, J=4.4 and 2.7 Hz, H-6'), 1.31 (6H, s, 2 x -CH3), 1.11 (9H, s, -tBu).
IR (nujol) υmax (cm-1): 2915, 2845, 1680 (C=O), 1595.
1H NMR 400 MHz (DMSO-d6) δ (ppm): 7.91 (2H, d, J=8.2 Hz, H-2 and H-6), 7.72 (2H, d, J=8.2 Hz, H-3 and H-5), 7.54 (1H, br d, J=8.0 Hz, H-3'), 7.42-7.34 (3H, m, vinyl H, H-1' and H-4'), 7.19 (1H, d, J=16.4 Hz, vinyl H), 6.01 (1H, br d, J=12.4 Hz, -CH=CH-tBu), 5.81 (1H, br s, H-7'), 5.70 (1H, d, J=12.4 Hz, -CH=CH-tBu), 2.26 (2H, br s, H-6'), 1.25 (6H, s, 2 x -CH3), 1.07 (9H, s, -tBu).
Anal. Calcd. for C27H30O2 | C 83.90; | H 7.82. |
Found | C 83.27; | H 7.73. |
1H NMR 400 MHz (CDCl3) δ (ppm): 0.84 (6H, t, J=7.5 Hz, 2 x -CH2CH 3), 1.15 (3H, s, -CH3), 1.47 and 1.65 (2 x 2H, 2m, 2 x -CH 2-CH3), 6.20 (1H, d, J=8.5 Hz, -CH=CHl), 6.36 (1H, d, J=8.5 Hz, =CHI).
1H NMR 400 MHz (CDCl3) δ (ppm): 0.75-0.97 and 1.27-1.53 (40H, 4 sets of m, 3 x -(CH2)3CH3, 2 x -CH2CH3 and -CH3), 5.71 (1H, d, J=14.2 Hz, -CH=), 6.45 (1H, d, J=14.2 Hz, =CH-Sn).
1H NMR 400 MHz (CDCl3) δ (ppm): 0.89 (6H, t, J=7.4 Hz, 2 x -CH2CH 3), 0.97 (3H, s, -CH3), 1.31 (6H, s, 2 x -CH3), 1.26-1.50 (4H, m, 2 x -CH 2CH3), 2.29 (2H, dd, J=4.4 and 2.7 Hz, H-6'), 3.93 (3H, s, -OCH3), 5.53 (1H, d, J=12.7 Hz, =CH-C(Et)2CH3), 5.83 (1H, dd, J=4.5 and 1.9 Hz, H-7'), 6.14 (1H, dq, J=12.7 and 2.3 Hz, -CH=CH-C(Et)2CH3), 7.08 and 7.20 (2 x 1H, 2 d, J=16.3 Hz, vinyl H), 7.33 (1H, d, J=7.9 Hz, H-4'), 7.38 (1H, dd, J=7.8 and 1.8 Hz, H-3'), 7.47 (1H, d, J=1.5 Hz, H-1'), 7.56 (2H, d, J=8.3 Hz, H-3 and H-5), 8.02 (2H, d, J=8.4 Hz, H-2 and H-6).
IR (nujol) υmax (cm-1): 2924, 2855, 1687 (C=O).
1H NMR 400 MHz (DMSO-d6) δ (ppm): 7.92 (2H, d, J=8.2 Hz, H-2 and H-6), 7.70 (2H, d, J=8.2 Hz, H-3 and H-5), 7.50 (1H, d, J=7.9 Hz, H-3'), 7.41 (1H, br s, H-1'), 7.37 (1H, d, vinyl H), 7.36 (1H, d, H-4'), 7.17 (1H, d, J=16.4 Hz, vinyl H), 6.17 (1H, br dq, J=12.7 and 2.0 Hz, -CH=CH-C(Et)2CH3), 5.79 (1H, br q, J=1.4 Hz, H-7'), 5.50 (1H, d, J=12.7 Hz, =CH-C(Et)2CH3), 2.26 (2H, br d, J=2.9 Hz, H-6'), 1.38 (4H, m, 2 x -CH 2CH3), 1.25 (6H, s, 2 x -CH3), 0.91 (3H, s, -CH3), 0.82 (6H, t, J=7.3 Hz, 2 x -CH2CH 3).
MS: 413.2 (MH)+.
1H NMR 400 MHz (CDCl3) δ (ppm): 8.04 (2H, d, J=8.4 Hz, H-2 and H-6), 7.98 (1H, d, J=1.8 Hz, H-1'), 7.60 (2H, d, J=8.3 Hz, H-3 and H-5), 7.43 (1H, dd, J=8.0 and 1.8 Hz, H-3'0, 7.35 (1H, d, J=7.9 Hz, H-4'), 7.26 and 7.14 (2 x 1H, 2 d, J=16.3 Hz, vinyl H), 6.39 (1H, t, J=4.7 Hz, H-7'), 3.94 (3H, s, -OMe), 3.20 (1H, m, J=6.7 Hz, -CH(CH3)2), 2.34 (2H, d, J=4.7 Hz, H-6'), 1.31 (6H, s, 2 x -CH3), 1.31 (6H, d, J=6.6 Hz, -CH(CH3)2).
IR (KBr) υmax (cm-1):3435, 2957,1682 (C=O), 1603.
1H NMR 400 MHz (DMSO-d6) δ (ppm): 7.93 (2H, d, J=8.4 Hz, H-2 and H-6), 7.84 (1H, d, J=1.6 Hz, H-1'), 7.73 (2H, d, J=8.4 Hz, H-3 and H-5), 7.59 (1H, dd, J=8.0 and 1.6 Hz, H-3'), 7.47 (1H, d, J=16.4 Hz, vinyl H), 7.38 (1H, d, J=8.0 Hz, H-4'), 7.25 (1H, d, J=16. 4 Hz, vinyl H), 6.34 (1H, t, J=4.7 Hz, H-7'), 3.21 (1H, m, J=6.6 Hz, -CH(Me)2), 2.30 (2H, d, J=4.7 Hz, H-6'), 1.25 (6H, s, 2 x -CH3), 1.24 (6H, d, J=6.5 Hz, -CH(CH 3)2).
MS: 377.07 (M-H)-.
Anal. Calcd. for C24H26O2S | C 76.15; | H 6.92. |
Found | C 75.89; | H 6.50. |
Claims (6)
- A pharmaceutical composition comprising a therapeutically effective amount of a retinoid compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
- A pharmaceutical composition comprising a therapeutically effective amount of a retinold compound of claim 2 and a pharmaceutically acceptable carrier or excipient
- Use of a compound of claim 1 for manufacturing a medicament for inhibiting tumor growth in a mammalian host.
- Use of a compound of claim 2 for manufacturing a medicament for inhibiting tumor growth in a mammalian host.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10160998P | 1998-09-24 | 1998-09-24 | |
US101609P | 1998-09-24 | ||
PCT/US1999/021598 WO2000017147A1 (en) | 1998-09-24 | 1999-09-16 | 5,6-dihydronaphthalenyl derivatives having retinoid-like activity |
Publications (3)
Publication Number | Publication Date |
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EP1115687A1 EP1115687A1 (en) | 2001-07-18 |
EP1115687A4 EP1115687A4 (en) | 2002-06-05 |
EP1115687B1 true EP1115687B1 (en) | 2004-05-26 |
Family
ID=22285543
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP99948322A Expired - Lifetime EP1115687B1 (en) | 1998-09-24 | 1999-09-16 | 5,6-dihydronaphthalenyl derivatives having retinoid-like activity |
Country Status (14)
Country | Link |
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US (1) | US6194601B1 (en) |
EP (1) | EP1115687B1 (en) |
JP (1) | JP2002526465A (en) |
CN (1) | CN1134405C (en) |
AT (1) | ATE267793T1 (en) |
AU (1) | AU761572B2 (en) |
BR (1) | BR9913925A (en) |
CA (1) | CA2344310A1 (en) |
DE (1) | DE69917660T2 (en) |
DK (1) | DK1115687T3 (en) |
ES (1) | ES2221754T3 (en) |
PT (1) | PT1115687E (en) |
TR (1) | TR200100858T2 (en) |
WO (1) | WO2000017147A1 (en) |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US5780676A (en) * | 1992-04-22 | 1998-07-14 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors |
US5648385A (en) * | 1994-01-03 | 1997-07-15 | Bristol-Myers Squibb Co. | Retinoid-like compounds |
US5648514A (en) | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes having retinoid-like biological activity |
US5489584A (en) * | 1994-12-29 | 1996-02-06 | Allergan, Inc. | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5514825A (en) * | 1994-12-29 | 1996-05-07 | Allergan, Inc. | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5618943A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5543534A (en) * | 1994-12-29 | 1996-08-06 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
US5599967A (en) * | 1994-12-29 | 1997-02-04 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity |
CA2258313A1 (en) * | 1996-06-21 | 1997-12-24 | Allergan Sales, Inc. | Substituted tetrahydronaphthalene and dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
-
1999
- 1999-09-16 DK DK99948322T patent/DK1115687T3/en active
- 1999-09-16 CA CA002344310A patent/CA2344310A1/en not_active Abandoned
- 1999-09-16 WO PCT/US1999/021598 patent/WO2000017147A1/en active IP Right Grant
- 1999-09-16 AU AU61528/99A patent/AU761572B2/en not_active Ceased
- 1999-09-16 TR TR2001/00858T patent/TR200100858T2/en unknown
- 1999-09-16 AT AT99948322T patent/ATE267793T1/en not_active IP Right Cessation
- 1999-09-16 CN CNB998112356A patent/CN1134405C/en not_active Expired - Fee Related
- 1999-09-16 JP JP2000574057A patent/JP2002526465A/en active Pending
- 1999-09-16 ES ES99948322T patent/ES2221754T3/en not_active Expired - Lifetime
- 1999-09-16 US US09/397,975 patent/US6194601B1/en not_active Expired - Fee Related
- 1999-09-16 PT PT99948322T patent/PT1115687E/en unknown
- 1999-09-16 EP EP99948322A patent/EP1115687B1/en not_active Expired - Lifetime
- 1999-09-16 DE DE69917660T patent/DE69917660T2/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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ES2221754T3 (en) | 2005-01-01 |
WO2000017147A1 (en) | 2000-03-30 |
DK1115687T3 (en) | 2004-09-20 |
EP1115687A1 (en) | 2001-07-18 |
CN1319083A (en) | 2001-10-24 |
BR9913925A (en) | 2001-06-19 |
DE69917660D1 (en) | 2004-07-01 |
AU6152899A (en) | 2000-04-10 |
CA2344310A1 (en) | 2000-03-30 |
EP1115687A4 (en) | 2002-06-05 |
ATE267793T1 (en) | 2004-06-15 |
CN1134405C (en) | 2004-01-14 |
TR200100858T2 (en) | 2001-10-22 |
JP2002526465A (en) | 2002-08-20 |
PT1115687E (en) | 2004-09-30 |
AU761572B2 (en) | 2003-06-05 |
US6194601B1 (en) | 2001-02-27 |
DE69917660T2 (en) | 2005-06-16 |
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